Paul J. Albert

Autoimmune disease in the era of the metagenome.

Studies of autoimmune disease have focused on the characteristics of the identifiable antibodies. But as our knowledge of the genes associated with the disease states expands, we understand that humans must be viewed as superorganisms in which a plethora of bacterial genomes - a metagenome - work in tandem with our own. The NIH has estimated that 90% of the cells in Homo sapiens are microbial and not human in origin. Some of these microbes create metabolites that interfere with the expression of genes associated with autoimmune disease. Thus, we must re-examine how human gene transcription is affected by the plethora of microbial metabolites. We can no longer assume that antibodies generated in autoimmune disease are created solely as autoantibodies to human DNA. Evidence is now emerging that the human microbiota accumulates during a lifetime, and a variety of persistence mechanisms are coming to light. In one model, obstruction of VDR nuclear-receptor-transcription prevents the innate immune system from making key antimicrobials, allowing the microbes to persist. Genes from these microbes must necessarily impact disease progression. Recent efforts to decrease this VDR-perverting microbiota in patients with autoimmune disease have resulted in reversal of autoimmune processes. As the NIH Human Microbiome Project continues to better characterize the human metagenome, new insights into autoimmune pathogenesis are beginning to emerge.

Vitamin D metabolites as clinical markers in autoimmune and chronic disease

Recent research has implicated vitamin D deficiency (serum levels of 25‐hydroxyvitamin D <50 nmol/L) with a number of chronic conditions, including autoimmune conditions such as multiple sclerosis, lupus, and psoriasis, and chronic conditions such as osteoporosis, osteoarthritis, metabolic syndrome, fibromyalgia and chronic fatigue syndrome. It has been assumed that low levels of 25‐hydroxyvitamin D (25‐D) accurately indicate vitamin D storage and vitamin D receptor (VDR)–mediated control of calcium metabolism and innate immunity. To evaluate this assumption, 25‐D and 1,25‐dihydroxyvitamin D3 (1,25‐D) levels were measured in 100 Canadian patients with these conditions. Additionally, other inflammatory markers (CK, CRP) were measured. Results showed a strong positive association between these autoimmune conditions and levels of 1,25‐D >110 pmol/L. However, there was little association with vitamin D deficiency or the other inflammatory markers, meaning that the results challenge the assumption that serum levels of 25‐D are a sensitive measure of the autoimmune disease state. Rather, these findings support the use of 1,25‐D as a clinical marker in autoimmune conditions. High levels of 1,25‐D may result when dysregulation of the VDR by bacterial ligands prevents the receptor from expressing enzymes necessary to keep 1,25‐D in a normal range.

The human microbiome and autoimmunity.

Purpose of reviewTo demonstrate how dysbiosis of the human microbiome can drive autoimmune disease. Recent findingsHumans are superorganisms. The human body harbors an extensive microbiome, which has been shown to differ in patients with autoimmune diagnoses. Intracellular microbes slow innate immune defenses by dysregulating the vitamin D nuclear receptor, allowing pathogens to accumulate in tissue and blood. Molecular mimicry between pathogen and host causes further dysfunction by interfering with human protein interactions. Autoantibodies may well be created in response to pathogens. SummaryThe catastrophic failure of human metabolism observed in autoimmune disease results from a common underlying pathogenesis – the successive accumulation of pathogens into the microbiome over time, and the ability of such pathogens to dysregulate gene transcription, translation, and human metabolic processes. Autoimmune diseases are more likely passed in families because of the inheritance of a familial microbiome, rather than Mendelian inheritance of genetic abnormalities. We can stimulate innate immune defenses and allow patients to target pathogens, but cell death results in immunopathology.

Reversing Bacteria‐induced Vitamin D Receptor Dysfunction Is Key to Autoimmune Disease

Vitamin D research is discussed in light of the hypothesis that the lower average levels of vitamin D frequently observed in autoimmune disease are not a sign of deficiency. Instead, it is proposed that the lower levels result from chronic infection with intracellular bacteria that dysregulate vitamin D metabolism by causing vitamin D receptor (VDR) dysfunction within phagocytes. The VDR dysfunction causes a decline in innate immune function that causes susceptibility to additional infections that contribute to disease progression. Evidence has been accumulating that indicates that a number of autoimmune diseases can be reversed by gradually restoring VDR function with the VDR agonist olmesartan and subinhibitory dosages of certain bacteriostatic antibiotics. Diseases showing favorable responses to treatment so far include systemic lupus erythematosis, rheumatoid arthritis, scleroderma, sarcoidosis, Sjogrens syndrome, autoimmune thyroid disease, psoriasis, ankylosing spondylitis, Reiters syndrome, type I and II diabetes mellitus, and uveitis. Disease reversal using this approach requires limitation of vitamin D in order to avoid contributing to dysfunction of nuclear receptors and subsequent negative consequences for immune and endocrine function. Immunopathological reactions accompanying bacterial cell death require a gradual elimination of pathogens over several years. Practical and theoretical implications are discussed, along with the compatibility of this model with current research.

Dysregulation of the Vitamin D Nuclear Receptor May Contribute to the Higher Prevalence of Some Autoimmune Diseases in Women

Researchers have noted that the incidence of autoimmune diseases, such as Hashimotos thyroiditis, is markedly higher in women than in men, but to date the reason for this disparity has been unclear. The vitamin D nuclear receptor (VDR) is expressed in the human cycling endometrium. Because the VDR controls expression of the cathelicidin and β‐defensin antimicrobial peptides (AmPs), dysregulation of the receptor greatly compromises the innate immune response. Increasing evidence indicates the presence of a chronic, intraphagocytic, metagenomic microbiota in patients with autoimmune disease that may survive by dysregulating the VDR. VDR dysregulation, in turn, prevents the breakdown of the active vitamin D metabolite 1,25‐hydroxyvitamin D (1,25‐D) by CYP24. In silico data suggest that when 1,25‐D rises above its normal range, it binds the α/β thyroid receptors, the glucocorticoid receptor (GCR), and the androgen receptor (AR), displacing their native ligands and causing an array of hormonal imbalances. If T3 is displaced from α‐thyroid, thyroiditis may result. Because the VDR, GCR, and AR also express multiple families of AmPs, expression of these natural antibiotics further wanes in response to dysregulation by 1,25‐D. The end result is a system‐wide drop in AmP expression that may allow pathogens to spread with greater ease. Because women have an extra site of VDR expression in the endometrium, the drop in AmP expression associated with nuclear receptor dysregulation may disproportionately affect them. This would cause women to accumulate higher bacterial loads than their male counterparts, particularly during early pregnancy when 1,25‐D levels rise by 40%.

Immunostimulation in the era of the metagenome

Microbes are increasingly being implicated in autoimmune disease. This calls for a re-evaluation of how these chronic inflammatory illnesses are routinely treated. The standard of care for autoimmune disease remains the use of medications that slow the immune response, while treatments aimed at eradicating microbes seek the exact opposite—stimulation of the innate immune response. Immunostimulation is complicated by a cascade of sequelae, including exacerbated inflammation, which occurs in response to microbial death. Over the past 8 years, we have collaborated with American and international clinical professionals to research a model-based treatment for inflammatory disease. This intervention, designed to stimulate the innate immune response, has required a reevaluation of disease progression and amelioration. Paramount is the inherent conflict between palliation and microbicidal efficacy. Increased microbicidal activity was experienced as immunopathology—a temporary worsening of symptoms. Further studies are needed, but they will require careful planning to manage this immunopathology.

Immunostimulation in the treatment for chronic fatigue syndrome/myalgic encephalomyelitis

Chronic fatigue syndrome (CFS)/myalgic encephalomyelitis (ME) has long been associated with the presence of infectious agents, but no single pathogen has been reliably identified in all patients with the disease. Recent studies using metagenomic techniques have demonstrated the presence of thousands of microbes in the human body that were previously undetected and unknown to science. More importantly, such species interact together by sharing genes and genetic function within communities. It follows that searching for a singular pathogen may greatly underestimate the microbial complexity potentially driving a complex disease like CFS/ME. Intracellular microbes alter the expression of human genes in order to facilitate their survival. We have put forth a model describing how multiple species—bacterial, viral, and fungal—can cumulatively dysregulate expression by the VDR nuclear receptor in order to survive and thus drive a disease process. Based on this model, we have developed an immunostimulatory therapy that is showing promise inducing both subjective and objective improvement in patients suffering from CFS/ME.

Autoimmune Disease and the Human Metagenome

The prevailing theory of autoimmune disease, that the body creates autoantibodies that attack “self,” was developed during an era when culture-based methods vastly underestimated the number of microbes capable of persisting in and on Homo sapiens. Thanks to the advent of culture-independent tools, the human body is now known to harbor billions of microbes whose collective genomes work in concert with the human genome. Thus, the human genome can no longer be studied in isolation. Some of these microbes persist by slowing the activity of the vitamin D receptor nuclear receptor, affecting the expression of endogenous antimicrobials and other key components of the innate immune system. It seems that bacteria that cause autoimmune disease accumulate over a lifetime, with individuals picking up pathogens with greater ease over time, as the immune response becomes increasingly compromised. Any one autoimmune disease is likely due to many different microbes within the metagenomic microbiota. This helps explain the high levels of comorbidity observed among patients with autoimmune conditions. What are commonly believed to be autoantibodies may instead be created in response to this metagenomic microbiota when the adaptive immune system is forced to deal with disintegration of infected cells. Similarly, haplotypes associated with autoimmune conditions vary widely among individuals and populations. They are more suggestive of a regional infectious model rather than a model in which an illness is caused by inherited variation of HLA haplotypes

Research discovery through linked open data

VIVO is an open source semantic web platform that contains information about scholars and their interests and activities. This demonstration will highlight the platform and ontology, data sources, features of the software and the ways that VIVO data can be leveraged for a variety of purposes within and beyond an institution to facilitate collaboration and research discovery.